Abstract Myelination of axons in the nervous system is critical for not only conduction of action potentials, but also for providing tropic support to ensure long term survival of neurons in both the central and peripheral nervous systems. Myelin disorders are a major cause of neurological disease, and can be caused by genetic disorders, infectious disease, and inflammation. Therefore, understanding the pathways that control gene expression patterns in myelinating cells is a critical step in not only elucidating developmental pathways, but also to provide insight into means by which remyelination after nerve injury can be accelerated. The peripheral nervous system has substantial plasticity in being able to regenerate after nerve injury, and critical transcription factors and their target gene networks have begun to be elucidated. Interestingly, recent studies have demonstrated that Schwann cell reprogramming to a new differentiated state is a critical and rate limiting factor in peripheral nerve regeneration. Although substantial progress has been made to identify gene expression changes that occur after injury, there have been relatively few studies examining the chromatin modifications required for Schwann cell reprogramming to the injured state. The long term objective of our laboratory is to elucidate an integrated mechanism of Schwann cell reprogramming after nerve injury based on critical microRNA and epigenomic switches that we have identified. Specifically, this proposal focuses on testing how reversal of the polycomb pathway is required for Schwann cell responses to peripheral nerve injury. Chromatin immunoprecipitation analyses will focus on epigenetic changes that occur during nerve injury, and test for the first time the involvement of histone demethylases in nerve injury responses. Finally, this proposal also takes advantage of several unique aspects of peripheral nerve, which facilitate the epigenomic analysis that we have proposed here.